Taina Hätönen

One-hour exposure to moderate illuminance (500 lux) shifts the human melatonin rhythm

Abstract: Salivary melatonin levels were measured in 12 healthy volunteers in order to determine whether a moderate light intensity, which suppresses the nocturnal rise of melatonin, was able to shift the melatonin rhythm. The samples were collected at 1‐hr intervals under lighting of < 100 lux (experiment 1) or < 10 lux (experiment 2). The control melatonin profiles were determined during the first night. In the second night the subjects were exposed to light of 500 lux for 60 min during the rising phase of melatonin synthesis. The third series of samples was collected during the third night. The mean decrease of melatonin levels by the exposure to light was 56% of the prelight concentrations. The melatonin onset times were delayed significantly (about 30 min) the night after the exposure to light. The melatonin offset times tended to be delayed in experiment 2. The shifts of the melatonin offset correlated positively with the amount of the melatonin suppression. The results suggest that a relatively small and short lasting light‐induced interruption of melatonin synthesis may affect the melatonin rhythm in humans.

Circadian Phenotype in Patients with the Co-Morbid Alcohol Use and Bipolar Disorders

AIMS Alcohol misuse is associated with bipolar disorder. Abnormalities in the circadian clockwork play a role in the pathogenesis of bipolar disorder. Alcohol intake is likely to affect the circadian phenotype. We aimed at analysing the behavioural trait of the preference to morning or evening hours for the daily activities in bipolar disorder patients with or without the co-morbid alcohol use. METHODS Our nationwide sample of families included patients with bipolar disorder born during 1940-1969 having at least one hospitalization due to bipolar disorder during 1969-1991 and their first-degree relatives. All the 148 participants were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders and assessed using the Morningness-Eveningness Questionnaire whose factor matrix applying for the maximum likelihood principle was calculated for the first time. RESULTS Patients with the co-morbid alcohol use disorder were more of the morning type as compared with patients with bipolar disorder only. CONCLUSIONS Co-morbid patients preferred more the morning hours for their daily activities, indicative of alcohol consumption having an effect on the circadian clock.

Melatonin, cortisol and body temperature rhythms in Lennox-Gastaut patients with or without circadian rhythm sleep disorders.

The daily rhythms of melatonin, cortisol and body temperature were studied in 16 institutionalized subjects with the Lennox-Gastaut syndrome. The results of 9 subjects with normal daily rhythms of sleep and wakefulness (group 1) were compared with those of 7 subjects with disordered sleep (group 2). Salivary samples were collected and axillary temperature was measured every 2 h during two or three separate 26-h periods. The hormones were measured by radioimmunoassays. The rhythms were characterized with single cosinor analysis. Two subjects in group 1 and six subjects in group 2 had abnormalities in their rhythms of temperature, cortisol or melatonin. All three rhythms were disrupted in two subjects of group 2. These two subjects were the only ones with disrupted cortisol rhythm. The diversity of rhythm pathologies suggested partly separate regulatory mechanisms for each rhythm. The co-occurrence of circadian rhythm sleep disorders with the deteriorated melatonin rhythm raised the question as to whether the sleep disorders of these subjects, like those of subjects with healthy brains, could be relieved by the induction of normal melatonin rhythm.

Suppression of melatonin by 2000-lux light in humans with closed eyelids

BACKGROUND In order to clarify the role of light in regulating body functions in sleeping humans, we studied whether the light-sensitive pineal hormone melatonin can be suppressed by facial light exposure in subjects with closed eyelids. METHODS Eight healthy volunteers participated in 3 nightly sessions: a dim-light control session (< 10 lux) and two light-exposure sessions (2000 lux, 60 min between 2400 and 0200 h). One light exposure occurred with eyes open and the other with eyes closed. Saliva samples were collected at least every hour from 1900 to 0300 h. Melatonin concentrations were measured by radioimmunoassay. RESULTS Salivary melatonin concentrations decreased only in 2 of the 8 volunteers during light-exposure sessions with eyes closed. On average, light exposure did not decrease the salivary melatonin concentration. CONCLUSIONS Because indoor illuminance is usually much lower than 2000 lux, light is probably ineffective in regulating the neuroendocrine hypothalamic functions in people during their sleep. Nevertheless, the possibility remains that higher illuminances, often used for therapeutic purposes, can inhibit the secretion of melatonin even in sleeping patients.

No evidence for extraocular light induced phase shifting of human melatonin, cortisol and thyrotropin rhythms

The view that light affects the mammalian circadian clock only through the eyes was recently challenged by a study in which the phases of human circadian rhythms were shifted by extraocular light exposure. This finding has not been confirmed, however. We studied the effects of light exposure (3 h, broad spectrum fluorescent white light, 13 000 lux) on abdomen and chest on the circadian rhythms of serum melatonin, cortisol and thyrotropin in six subjects. The protocol consisted of two 3-day sessions in a dimly lit (< 10 lux) experimental unit. In both sessions hourly serum samples were collected for hormone analysis on days 1 and 3. The skin light exposure was delivered on day 2 from 22.00 to 01.00 h in one of the two sessions in a randomized order. In both sessions all three rhythms tended to delay, presumably due to the endogenous circadian cycle length being slightly longer than 24 h. However, the phase shifts did not differ significantly between the sessions. Thus, the present study does not support the existence of extraocular photic regulation of the circadian rhythms in humans.

Bright light exposure of a large skin area does not affect melatonin or bilirubin levels in humans

BACKGROUND Light treatment through the eyes is effective in alleviating the symptoms of some psychiatric disorders. A recent report suggested that skin light exposure can affect human circadian rhythms. Bilirubin can serve as a hypothetical blood-borne mediator of skin illumination into the brain. We studied whether bright light directed to a large body area could suppress the pineal melatonin secretion or decrease serum total bilirubin in conditions that could be used for therapeutic purposes. METHODS Seven healthy volunteers participated in two consecutive overnight sessions that were identical except for a light exposure on the chest and abdomen in the second night from 12:00 AM to 6:00 AM (10,000-lux, 32 W/m(2) cool white for six subjects and 3000-lux, 15 W/m(2) blue light for one subject). Hourly blood samples were collected from 7:00 PM to 7:00 AM for melatonin radioimmunoassays. Bilirubin was measured by a modified diazo method in blood samples taken at 12:00 AM and 6:00 AM and in urine samples collected from 7:00 PM to 11:00 PM and from 11:00 PM to 7:00 AM. RESULTS The skin light exposure did not cause any significant changes in serum melatonin or bilirubin levels. The excretion of bilirubin in urine was also the same in both sessions. CONCLUSIONS Significant melatonin suppression by extraocular light does not occur in humans. Robust concentration changes of serum total bilirubin do not have a role in mediating light information from the skin to the central nervous system.

Exogenous melatonin fails to counteract the light-induced phase delay of human melatonin rhythm

Salivary melatonin levels were measured in 6 healthy volunteers in order to determine whether the phase shift caused by a single 60-min light pulse of 2000 lux might be inhibited by maintaining high melatonin concentration. In the control sessions, the samples were collected at 60-min intervals under lighting of < 10 lux from 18.00 to 11.00 h. In the light-exposure sessions, placebo or 0.5 mg melatonin was administered orally 60 min prior to the light pulse, timed at the rising phase of the melatonin synthesis. The after-light sessions, one day after the light exposure, were like the control sessions. The average delays of the melatonin half-rise and half-decline times were equal (about 0.7 h) in the placebo and melatonin replacement experiments. The maintenance of high melatonin levels during the light exposure did not counteract the influence of bright light on the melatonin rhythm. Thus, in the adjustment of the melatonin rhythm, light is a stronger regulator than melatonin itself.

Lithium is associated with decrease in all-cause and suicide mortality in high-risk bipolar patients: A nationwide registry-based prospective cohort study

BACKGROUND Mortality rates, in particular due to suicide, are especially high in bipolar patients. This nationwide, registry-based study analyses the associations of medication use with hospitalization due to attempted suicides, deaths from suicide, and overall mortality across different psychotropic agents in bipolar patients. METHOD Altogether 826 bipolar patients hospitalized in Finland between 1996-2003 because of a suicide attempt were followed-up for a mean of 3.5 years. The relative risk of suicide attempts leading to hospitalization, completed suicide, and overall mortality during lithium vs. no-lithium, antipsychotic vs. no-antipsychotic, valproic acid vs. no-valproic acid, antidepressant vs. no-antidepressant and benzodiazepine vs. no-benzodiazepine treatment was measured. RESULTS The use of valproic acid (RR=1.53, 95% CI: 1.26-1.85, p<0.001), antidepressants (RR=1.49, 95% CI: 1.23-1.8, p<0.001) and benzodiazepines (RR=1.49, 95% CI: 1.23-1.80, p<0.001) was associated with increased risk of attempted suicide. Lithium was associated with a (non-significantly) lower risk of suicide attempts, and with significantly decreased suicide mortality in univariate (RR=0.39, 95% CI: 0.17-0.93, p=0.03), Cox (HR=0.37, 95% CI: 0.16-0.88, p=0.02) and marginal structural models (HR=0.31, 95% CI: 0.12-0.79, p=0.02). Moreover, lithium was related to decreased all-cause mortality by 49% (marginal structural models). LIMITATIONS Only high-risk bipolar patients hospitalized after a suicide attempt were studied. Diagnosis was not based on standardized diagnostic interviews; treatment regimens were uncontrolled. CONCLUSIONS Maintenance therapy with lithium, but not with other medications, is linked to decreased suicide and all-cause mortality in high-risk bipolar patients. Lithium should be considered for suicide prevention in high-risk bipolar patients.

Pineal melatonin in rats: suppression by the selective α2-adrenoceptor agonist medetomidine

This study was done to clarify the role of alpha2-adrenoceptors in the regulation of pineal melatonin synthesis. A selective alpha2-adrenoceptor agonist, medetomidine, and antagonist, atipamezole, were injected subcutaneously into rats and their pineal melatonin contents were measured by radioimmunoassay. Medetomidine (120 microg/kg) suppressed melatonin at night to a similar extent during the rising and descending phase of melatonin synthesis, but it did not affect the daytime level. A dose of 12 microg/kg was ineffective; doses of 30-180 microg/kg suppressed nocturnal melatonin levels close to the daytime levels. Significant suppression was reached within 15 min and the effect started to fade 3 h after the injection (120 microg/kg). At midday, medetomidine did not inhibit isoproterenol-stimulated synthesis of melatonin. Atipamezole (0.4 or 1.2 mg/kg) had no effect alone, but it counteracted the medetomidine-induced suppression. The effects of alpha2-adrenoceptor ligands on melatonin synthesis depend on the time of day and/or on the activity of the pineal sympathetic nerves.

Daytime dark exposure increases pineal melatonin in rat pups

Abstract: Photic regulation of the pineal melatonin synthesis was studied in 3‐ to 21‐day‐old rat pups by exposing the animals to light at night (30–40 min) or to darkness during the day (30–240 min). The pineal melatonin contents were measured by radioimmunoassay. A significant day/night difference in the melatonin content and the nocturnal light‐induced decrease were not found until second postnatal week. A novel finding was that at the age of 13–17 days a daytime dark exposure elevated the pineal melatonin content; it was twofold as compared with the normal daytime level and about half of the nocturnal peak level. In 21‐day‐old rats the response had disappeared, while the nocturnal suppression by light persisted. The dark‐induced increase of the melatonin synthesis was independent of the opening of the eyelids which occurs in pups at the age of two weeks, but it was greater in maternally isolated than non‐isolated pups. The results suggest that one component of the circadian regulatory system matures at the end of the third postnatal week. This mechanism inhibits the elevation of the melatonin synthesis by darkness during the daytime.